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Polymer conjugated prostaglandin analogues

A prostaglandin and polymer technology, which is applied in the direction of drug combination, eicosanoid active ingredients, medical preparations of non-active ingredients, etc., can solve the problems of patient compliance and other problems

Inactive Publication Date: 2014-05-21
POLYACTIVA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, patient compliance in glaucoma treatment is problematic

Method used

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  • Polymer conjugated prostaglandin analogues
  • Polymer conjugated prostaglandin analogues
  • Polymer conjugated prostaglandin analogues

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0697] (Z)-3-Hydroxy-2-(hydroxymethyl)-2-methylpropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3 -Hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate (2)

[0698]

[0699]Following the general procedure for HBTU coupling (Procedure 1), use latanoprost free acid (1) (407.1 mg, 1.0 mmol), HBTU (440.3 mg, 1.2 mmol), 1,1,1-trihydroxymethyl A solution of ethyl ethane (187.9 mg, 1.6 mmol) and triethylamine (0.60 mL, 4.3 mmol) in anhydrous THF. Chromatography of the residue (SiO 2 , MeOH-CHCl 3 , 10:90), the title compound (2) (322.0 mg, 63% yield) was obtained as a colorless clear oil. ESI-MS: m / z 538 ([M+2Na] + ); 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.34-7.16 (m, 3H), 7.16-7.00 (m, 2H), 5.43-5.36 (m, 1H), 5.35-5.18 (m, 1H), 4.16-3.97 (m, 2H) , 3.89-3.74 (m, 1H), 3.61-3.51 (m, 1H), 3.45 (s, 3H), 3.41-3.31 (m, 4H), 2.80-2.65 (m, 2H), 2.65-2.46 (m, 2H), 2.40-1.96 (m, 5H), 1.91-1.35 (m, 8H), 1.35-1.20 (m, 2H), 0.77 (s, 2H).

Embodiment 2

[0700] Example 2 (Z)-1,3-dihydroxypropan-2-yl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxyl-5 -Phenylpentyl)cyclopentyl)hept-5-enoate (5)

[0701]

[0702] Following the general procedure for HBTU coupling (Procedure 1), use latanoprost free acid (1) (528.2 mg, 1.35 mmol), 1,3-benzylidene glycerol (309.0 mg, 1.71 mmol), HBTU ( 564.5mg, 1.49mmol), and triethylamine (0.8ml, 5.75mmol) in anhydrous DCM. Chromatographic analysis of the crude material (SiO 2 , EtOAc, 100%), the benzylidene ester (3) was obtained as a colorless clear oil (412.3 mg, 55% yield). ESI-MS: m / z 575 ([M+Na] + ); 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.49-7.37 (m, 2H), 7.37-7.24 (m, 3H), 7.24-7.16 (m, 2H), 7.16-7.03 (m, 3H), 5.48 (s, 1H), 5.41 -5.31 (m, 4H), 4.70-4.57 (m, 1H), 4.26-3.94 (m, 5H), 3.90-3.69 (m, 1H), 3.81-3.82 (m, 1H), 2.77-2.64 (m, 1H), 2.62-2.54 (m, 1H), 2.38 (td, J=7.2, 1.2Hz, 3H), 2.30-1.98 (m, 6H), 1.82-1.35 (m, 10H), 1.35-1.13 (m, 2H).

[0703] Following the general procedure ...

Embodiment 3

[0705] 1,3-dihydroxypropan-2-yl 4-(((Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy- 5-phenylpentyl)cyclopentyl)hept-5-enoyl)oxy)benzoate (6)

[0706]

[0707] Following the general procedure for HBTU coupling (Procedure 1), use latanoprost free acid (1) (234.1 mg, 0.60 mmol), 2-phenyl-1,3-dioxan-5-yl 4-hydroxy A solution of benzoate (361.5mg, 1.20mmol), HBTU (251.4mg, 0.66mmol) and triethylamine (0.5ml, 3.59mmol) in anhydrous DCM (15ml). Chromatographic analysis of the crude material (SiO 2 , EtOAc, 100%), the benzylidene ester (4) was obtained as a colorless clear oil (258.7 mg, 63% yield). ESI-MS: m / z695 ([M+Na] + ); 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.17-8.04 (m, 2H), 7.55-7.40 (m, 2H), 7.40-7.25 (m, 3H), 7.25-7.16 (m, 2H), 7.16-7.02 (m, 5H) , 5.55 (s, 1H), 5.50-5.26 (m, 2H), 4.94-4.79 (m, 1H), 4.41-4.12 (m, 4H), 4.12-3.97 (m, 1H), 3.93-3.79 (m, 1H), 3.65-3.49 (m, 1H), 2.73-2.55 (m, 2H), 2.43-2.06 (m, 5H), 1.87-1.38 (m, 13H), 1.38-1.22 (m, 2H).

[0708] Fol...

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Abstract

The present invention relates in general to polymer-drug conjugates. In particular, the invention relates to polymer-drug conjugates wherein the conjugated drugs are selected from prostaglandins and substituted prostaglandins, to a method of delivering such prostaglandin drugs to a subject, to a sustained drug delivery system comprising the polymer-drug conjugates, to a method of preparing the polymer-drug conjugates, and to an implant comprising the polymer-drug conjugates. The polymer-drug conjugates may be useful for delivering prostaglandins and substituted prostaglandins for the treatment of glaucoma.

Description

technical field [0001] The present invention relates generally to polymer-drug conjugates. In particular, the present invention relates to: polymer-drug conjugates, wherein the conjugated drug is selected from prostaglandins and substituted prostaglandins; methods of delivering such drugs to a subject; comprising said polymer- Sustained drug delivery systems for drug conjugates; methods of making the polymer-drug conjugates; and implants comprising the polymer-drug conjugates. Background technique [0002] Targeted and controlled drug delivery is currently an area of ​​great interest. Delivery of drugs to a subject in a site-specific manner is a highly desirable feature for the treatment of many different conditions. Implanting a drug-containing device into a subject (human or animal) can desirably improve the efficacy and safety of the drug. Specific sites within a subject may require sophisticated delivery devices to overcome barriers to effective drug delivery. For ex...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61P27/06A61K31/557C07C405/00
CPCC07C405/00A61K47/595A61P27/06A61K47/50A61K31/557
Inventor 迈克尔·沙恩·奥谢弗洛里安·汉斯·马克西米利安·格拉契拉塞尔·约翰·泰特安德鲁·克雷格·多诺霍吴敏仪阿沙·玛丽娜·德索萨
Owner POLYACTIVA
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